DE3242665A1 - DERIVATIVES OF 1,4-THIAZANE-3-CARBONIC ACID, THE PRODUCTION AND USE THEREOF AND PREPARATIONS CONTAINING THESE DERIVATIVES - Google Patents

Description

Derivatives of 1, ^/ + - 'rhiaznn-3-carboxylic acid, their production and use and preparations containing these derivatives

The present invention relates to derivatives of 1/! -Tbiazanecarboxylic acid and the salts of these compounds, Process for their production and also pharmaceutical preparations which contain at least one of these Derivatives included, and methods of using them.

The V ('. Rt'ahren nach der isri'indunp; Rehorchen the general Shape]

in which

Κη and Rp, which can be the same or different, Hydrogen, a linear or branched alkyl radical

with 1, 2, 3 or 4 carbon atoms or a phenyl radical, the optionally with a halogen atom such as fluorine, chlorine or bromine, with a linear or branched alkyl radical 1, 2, 3 or 4 carbon atoms or a linear or branched alkoxy radical is substituted with 1, 2, 3 or 4 carbon atoms, or but

R ,, and Ep with the adjacent carbon atom form a cycloalkyl radical with 3 »4, 5» 6, 7 or 8 carbon atoms, of which one or more carbon atoms are optionally replaced by sulfur, oxygen or a group SO, S0 ~ or NRo can be replaced, where in the latter Rg denotes hydrogen, a linear or branched alkyl radical with 1, 2, 3 or 4 carbon atoms, a phenyl radical or a benzyl radical,

R ^ is a hydroxyl group, a group ORQ, in which Rq is a linear or branched alkyl group having 1, 2, 3, 4, 5, 6, 7, 8, 9, 1O ₁ 11 or 12 carbon atoms or a group 0-CH -COOR ^ or a group OCH-OGOR ^ ₁ means,

in which R ^ q is hydrogen or an alkyl radical with 1 or 2 carbon atoms and R ^ _{1 is} a linear or branched alkyl radical with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 C -Atoms means in which further

can be a group N ^^,

^E 13

in which R ^ o ^{un <} ^ ^ 13 »^ ^{e can be} identical or different, hydrogen or a linear or branched one

Alkyl radical with 1, 2, 3 or 4 carbon atoms, a 3-phthalidyloxy or a 1- (2,5-dioxopyrrolidinyl) -1-ethoxy group,

R ^. Hydrogen, a linear or branched alkyl radical with 1, 2, 3, 4-, 5 »6, 7 or 8 carbon atoms, a linear one or branched acyl radical with 1, 2, 3 ». 4 · »5t 6, 7 or 8 carbon atoms, or the group CONHp denotes, or

R * and R ₁ ^ form a hydantoin ring with the neighboring carbon and nitrogen atoms,

R ₁ - and rL-, which can be identical or different, are hydrogen, a linear or branched alkyl radical with 1, 2, 3, 4, 5, G, 7 or 8 carbon atoms, one optionally with a halogen atom such as fluorine or chlorine or bromine, with a linear or branched alkyl radical with 1, 2, 3 or 4 carbon atoms or with a linear or branched alkoxy radical with 1, 2, 3 or 4 carbon atoms substituted Pheyl radical or a group CHpCOOR ^^ in which R ^ is hydrogen or a linear or branched alkyl radical with 1, 2, 3 or 4 carbon atoms,

R “is hydrogen, a linear or branched alkyl group with 1, 2, 3 or 4 carbon atoms, a gem-dimethyl group or one with a halogen atom such as fluorine, chlorine or bromine, with a linear or branched alkyl radical with 1, 2, 3 or 4 carbon atoms or with a linear or branched alkoxy radical with 1, 2, 3 or 4 atoms, substituted phenyl radical,

has the value 0.1 or 2,

and Eg denote neither hydrogen nor a linear or branched alkyl radical having 1 to 4 carbon atoms or a phenyl radical when R ₁ , R £, R ^ and R ₁ -, are each oxygen and R is the hydroxyl group or a linear or ver branched alkyl radical with 1 to 4 carbon atoms.

According to a preferred form of the invention, this relates to the compounds of the formula (I) in which

R ^ and Rp, which can be the same or different, are hydrogen or a linear or branched alkyl radical with 1 to 4 carbon atoms,

R, the hydroxyl group, a group ORq in which Rq is a linear or branched alkyl radical with 1 to 4 carbon atoms, a group O-CH-COC-R ^ ^ or a group OCH-OCOR ₁ ,,

r \, means in which R ^ q is hydrogen or the methyl radical and "Άλλ is a linear or branched alkyl radical with 1 to 8 carbon atoms,

IL hydrogen or the methyl radical bleutet,

R _n . and R ₆ , which can be the same or different, are hydrogen or a linear or branched alkyl radical

1 to 4 · C atoms or a group CHpCOOR ^ in which R ^ ₁ , hydrogen or an alkyl group with 1 or

2 carbon atoms is

R ₇ means hydrogen,

N is 0 or 1.

A preferred class of compounds according to formula (I) is those in which R ^ and R ^ are hydrogen or a methyl group,

R ^ denotes a hydroxyl group or a group ORq, in which Rq has a linear or branched alkyl group Is 1 to 4 carbon atoms,

R _Li Vasserscoff or the methyl group means

Rt- hydrogen means and

R _fi denotes a linear or branched alkyl group with 1 to 4 G atoms,

Rn is hydrogen and

η can have the values 0 or 1.

Examples of compounds according to the invention are:

i-Oxo-2,2,5-trimethyl-1,4-tbiazan-3-carboxylic acid ethyl ester,

2,2,4,5-tetramethyl-1,4-thiazane-3-carboxylic acid, 1- (pivaloxyloxy) ethyl ester of i-oxo-2,2,5-trimethyl-1,4-thiazane-carboxylic acid,

i-Oxo-2,2,5-trimethyl-1,4-thiazane-3-carboxylic acid octyl

oxycarbonyl methyl ester,

i-Oxo-2,2,5-trimethyl-1,4-thiazane-3-carboxylic acid-1-ethyl-

oxycarbonylethyl ester,

5-butyl-2,2-dimethyl-1, A-thiazane-3-carboxylic acid,

2,2-dimethyl-5-isopropyl-1,4-thiazane-5-carboxylic acid,

5 methyl-2-phenyl-1, ^ - thiazan ^ -carboxylic acid,

3-Carboxy-2,2-dimethyl-1,4-thiazane-5-acetic acid ethyl ester.

When the derivatives of the formula (I) are in the form of To present acid addition salts, they can be converted into their free base or salts with others by customary methods React acids.

The most frequently used salts are the addition salts non-toxic and pharmaceutically acceptable acids formed with suitable inorganic acids, for example with hydrochloric acid, sulfuric acid or phosphoric acid, or with suitable organic acids, such as aliphytic, cycloaliphatic, aromatic, araliphatic or hefcerocyclic carboxylic or sulphonic acids, such as formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, Tartaric acid, citric acid, ascorbic acid, glucuronic acid, Maleic acid, fumaric acid, pyrovonic acid, aspartic acid, Glutamic acid, benzoic acid, anthranilic acid, hydroxybenzoic acid, salicylic acid, phenylacetic acid, mandelic acid, Emboxylic acid, methanesulfonic acid, ethanesulfonic acid, Pantothenic acid, tuluenesulphonic acid, sulphanilic acid, cyclöh exyl amino sulfonic acid, stearic acid, alginic acid, ß-hydroxypropionic acid, ß-hydroxybutyric acid, oaxalic acid, malonic acid, galactaric acid and galacturonic acid. These salts can can also be derived from natural or artificial amino acids, such as lysic acid, glycic acid, arginic acid, Oraltic acid, aspartic acid, glutamic acid, alanic acid, Valic acid, trionic acid, seric acid, leucine sour, Cysteic acid, etc.

If Rz stands for the group OH, this includes The invention also relates to the salts between this carboxylic acid function of the formula (I) thus obtained and bases are formed, such as in the hydroxide of sodium, potassium, lithium, ammonium, magnesium and calcium, as well as the internal salts (zwitterions).

The compounds of the formula (I) can occupy one or more centers of asymmetry and are in the form of optical or Racemic isomers as well as diastereoisomers exist · All of these forms are part of the present invention. The optical isomers can be stereospecific or obtained stereoselective synthesis or by separating racemic mixtures according to classical methods are, for example, by the formation of diastereoisomeric salts by the action of optically active acids, such as Tartaric acid, diacetyltartaric acid, tartranilic acid, the Dibenzoyltartaric acid, the ditoluoyltartaric acid, and separation the mixture of the diastereoisomers, for example by crystallization or chromatography, and then Release of the optically active bases including these salts. The optically active compounds of the formula (I) can can also be obtained by using optically active starting materials. Mixtures of diastereoisomers can be separated in the same way as the above-mentioned diastereoisomeric salts.

Thromboses and arterial and venous affections are currently a major cause of death and, in particular, disease in the west. The products according to the invention allow a novel therapeutic treatment which on those with substances which on the one hand affect the function of the blood platelets and on the other hand act on the fibrinolysiscnen enzymes. An increase the fibrinolytic effect of the blood, which is an increase the synthesis and / or the release of natural activators of fibrinolysis follows and the result of the oral or parenteral administration of the products according to the invention, allows a significant therapeutic Use under greatly increased security conditions. So can deep venous thrombosis and their frequent fatal consequences, namely pulmonary embolism, from treatment be prevented in which the substances in the weeks before and after a risky surgical procedure administered orally.

Likewise, preventive treatment against thrombosis as a complication of superficial, primary or secondary Phlebitis with prolonged immobilization of patients should also be considered. The substances according to the invention can also be used under circumstances in which a decrease in the fibrinolitic Blood activity occurs, such as after surgery, during general anesthesia or in the case of insulin-treated diabetes,

Finally, the products according to the invention, alone or in conjunction with substances, that promote adhesion and aggregation Prevent the platelet from appearing to prevent incidents which may result in recurrent arterial or venous thrombosis. It is known that this occurs in patients who have a brain or coronary thrombosis (Myocardial infarction) have suffered the danger relapse justifies the use of preventive therapy.

The products of the invention are effective when administered orally, which allows and can be easy to use over long periods of time are entered, in contrast to the current fibrinolytic substances because they do not have an enzymatic effect, do not cause immunity and act through activators normally found in the Organism. Their use, alone or in conjunction with substances that inhibit platelets, allows a new approach in the treatment and prevention of arterial and venous thrombosis.

The present invention equally claims pharmaceutical ones Compositions which contain at least one compound of the general formula (I) as an active ingredient and / or one of their salts in combination with a pharmaceutical carrier. These preparations are presented in such a way that they can be administered by the oral, rectal or parenteral routes.

"""" 3242666

For example, the preparations for oral administration can be liquid or solid and can be in shape of tablets, capsules, granules, powders, syrups or suspensions. Such preparations contain the additives and excipients as they are usually used in galenic pharmacy, neutral diluents, disintegrants, binders and lubricants such as lactose, starch, talc, gelatin, stearic acid, silica, Magnesium stearate, polyvinylpyrrolidone, calcium phosphate, Potassium carbonate, etc.

Such preparations can be carried out in such a way be that the time of disintegration and, consequently, the duration of action of the active ingredient is prolonged will.

Aqueous solutions, emulsions and oily solutions are, for example, with the addition of fillers such as dextrose and glycerol, and fragrances such as vanilin and may also contain thickeners, wetting agents and preservatives.

Emulsions and oily solutions become more vegetable with an oil or of animal origin and can contain emulsifiers, odorants, dispersants, sweeteners and contain antioxidants.

For parenteral administration it is used as a carrier sterile water, an aqueous solution of polyvinylpyrrolidone, peanut oil, ethyl oleate, etc. Such injectables

'to

aqueous or oily solutions can contain thickeners, Contain wetting agents, dispersants and gelling agents.

The compounds according to the invention are prepared by processes which are part of the present invention and are defined below. If in these procedures New intermediates are generated, these are new compounds as well as the processes involved in their manufacture are also part of the present invention.

According to a first type of process, a vinyl thioether is used of formula (II), which is derived from the method described by A.I. Virtanen et al, in Acta Ghem. Scand., 1966, 20, 1165-1185 Method is obtained, cyclized to the compound (III) according to the following scheme:

R _{1 rn} .D ^! '■ Ji COR R ₂ -C-CH y ^

T " ⁴

H * , Hp, R- ,, H ^, H ₁ -, H,., R ,. and η i.'urilen to represent def'i ned

324266b

The cyclization is preferably carried out in a basic medium. The base can be organic, such as triethylamine, pyrridine, Ν, Ν-dimethylaniline, or inorganic, such as Dialkali metal hydroxides, such as sodium or potassium hydroxide or ammonium hydroxide.

When the base used is an inorganic base, an inert organic one is preferably used as the solvent Solvents used, for example chlorinated solvents such as chloroform or dichloromethane, aromatic or aliphatic hydrocarbons such as benzene, toluene or the various fractions of petroleum ether, or else such solvents as acetonitrile, N, N-dimethylformamide or dimethyl sulfoxide.

If it is an inorganic base, the solvent used is preferably water and the The concentration of the basic solution is 0.01 N to 10 N and advantageously between 0.2 N and 2 N.

The reaction takes place at a temperature between ⁰ ° C. and the reflux temperature of the solvent. ! ■.: ·. however, it is particularly advantageous to operate at a temperature which is close to ambient temperature, especially if the starting materials or the products contain a predominant stereoisomer which tends to isomerization if the conditions used are too extreme.

Another type of procedure; consists of a Zyklisa Lion, to be carried out starting from a cysteine derivative (III), obtained by the method described by J.F. Carbon et al "J. Orfs. Chem. 2 £, '2203 (1964) was, according to the following ochema

(in) (D

In this scheme, R ^, lU »Rz» H ^. » Kc »ß ^» Ro and ri the meanings given above, while X is a halogen atom such as chlorine, bromine or iodine, a hydroxyl group or an easily eliminable group such as a tosyl or hesyl group.

AT

If the cyclization takes place in a basic environment, the conditions described for the first method can also be applied to the present case will·

If the cyclization takes place in an acidic medium, an inorganic or organic acid such as Hydrochloric acid, hydrobromic acid, hydriodic acid, Phosphoric acid, sulfuric acid, formic acid or acetic acid.

You can also use dehydrating agents such as the hemipentoxide of phosphorus, concentrated sulfuric acid, or a carbidiimide such as dicyclohexylcarbodiimide.

The reactions generally take place in inert organic solvents, for example chlorinated ones Solvents such as chloroform, dichloromethane, in aromatic or aliphatic hydrocarbons such as benzene, Toluene, xylene, chlorobenzene, dichlorobenzene or petroleum ether, or in solvents such as dimethyl sulfoxide or Ν, Ν-dimethylformamide. The reaction takes place in one Temperature instead of that between the ambient temperature and the reflux temperature of the chosen solvent lies.

Another type of procedure is a cysteine divab (IV) by reaction with a 0 (-halogen ketone (V,) cyclized. An unsaturated cyclic compound (VI) is formed, which then becomes the derivative (VlI) is reduced according to the following scheme:

- yt-

? 1 HS-C - CH - COR ₃ + Y-CH-CO-R,

Ro NHo R7

R ₅ ^ N ^ ^ ^0R 3

(IV)

(V)

(VI)

reduction

(VII)

R ^., Rp, R, R ₁ - and R ^ have been defined above. Ϊ means a halogen atom like chlorine, bi'om or iodine.

The first step of the process takes place in a neutral organic solvent, for example in one Alcohol such as methanol, ethanol or propanol, in an ether such as dioxane or tetrehydrofuran, or in a solvent such as dimethyl sulfoxide, N, N-dimethylformamide, or in aromatic hydrocarbons such as benzene or toluene.

The bases can be alkali metal hydroxides such as sodium or potassium hydroxide, alkali metal alcoholates such as, for example Sodium or potassium ethoxides, sodium or potassium ethoxides or use sodium or potassium t-butanolates.

The reaction takes place at a temperature between - is 20 ⁰ C and the reflux temperature of the solvent. It is advantageous to work at a temperature between ⁰ ° C. and ambient temperature.

A dehydrating agent can be used with advantage of the reaction mixture add, such as a molecular sieve.

The compound (VI) can be isolated and purified. But it can also be the raw mixture directly for the Reduction step can be used.

The imine (VI) is reduced in the presence of hydrogen and a hydrogenation catalyst such as platinum, platinum oxide or palladium on carbon in a solvent such as methanol, Ethanol, ethyl acetate or glacial acetic acid, at normal pressure or preferably at elevated pressure: or you

by means of an alkali metal hydride such as sodium borohydride in a solvent such as methanol, or by means of lithium aluminum hydride in a solvent such as ether or tetrahydrofuran.

Generally this reduction takes place at ambient temperature. Depending on the responsiveness of the system, it can however, it can sometimes be advantageous to heat or cool the reaction mixture.

In some cases, an acid such as Hydrochloric acid, sulfuric acid or acetic acid can be used to catalyze the reaction.

Means can be used to obtain the sulfoxides such as iodine, bromine in water or in the presence of acetate ions or in a complex with pyridine, peracids such as peracetic acid, Monoperphthalic acid or m-chloroperbenzoic acid, N-halosuccinimides such as N-bromosuccinimide, hypochlorites such as sodium hypochlorite, t-butyl hypochlorite or i-propyl hydrochlorite, Periodates such as sodium periodate, hydrogen peroxide in the presence of acetic anhydrite or in the presence of the hemipentoxide of vanadium in t-butanol, Nitrates such as acetyl nitrate or ammonium cerium nitrate, oxides like (VI) oxide in pyridine or hemipentoxide of vanadium in the presence of oxygen or the hemipentoxide of Nitrogen, peroxides, ozone, oxygen in the singlet or triplet state, acids such as nitric acid, chromic acid or caroic acid or other agents such as sulfuryl chloride,

- 324266S

1-chlorobenzotriazole, chloramine, N-chloronylon 66, iodobenzene dichloride, Iodosobenzene, iodobenzene diacetate, N-chlorotrialzene, 2,4,4,6-tetrabromocyclohexadienone or chloroauric acid (HAuCl ^). These oxidation reactions take place in solvents such as water, acetic acid, Chloroform, dichloromathane, carbon tetrachloride, methanol, t-butanol or acetone.

In order to obtain sulfones, it is advantageous to use them Active ingredients such as hydrogen peroxide, preferably in the presence of zirconium salts, peracids such as peracetic acid, Monoperphthalic acid or m-chloroperbenzoic acid (in the case For the oxidation with peracids, it is advantageous to use catalysts based on the transition metals, potassium permanganate in an acidic or basic medium, sodium or potassium dichromate, osmium tetraoxide, selenium oxide, t-butyl hypochlorite, Nitric acid, ozone, oxygen, advantageously in the presence of iridium or rhodium salts, the Dichloride of iodobenzene, periodic acid or an electrochemical one Oxidation · These reactions take place in solvents such as water, acetic acid, chloroform, dichloroethane, methanol, ethanol, isopropanol, t-butanol, dioxane or Acetone instead.

In some cases it can be advantageous to use the oxidation reactions described above for compounds in which the functions that are sensitive to the oxidizing agent used are protected.

The steps of cyclization, reduction and oxidation described below can also be part of a continuous process and do not require the isolation of intermediate products.

It should be noted that the transformation of a derivative (I), where η = * 0, into a derivative (I), where η = 1.2 at any stage in the preparation of the 1,4-thiazane cycle can be done.

Introducing the IL substituent when it is linear or a branched alkyl group with 1 to 8 carbon atoms or a linear or branched acyl group with 1 to 8 carbon atoms means, is carried out by alkylation or acylation of the amine according to the scheme:

1 COR-, D rna

1 ³ R 1> ^ÜK

1-5 η

R ₇ R

(VIII) (IX)

, R ₀ , R ₇ , R ₁ , R ₁ -, R ₇ and η have been defined above.

Z denotes a halogen atom such as chlorine, bromine or iodine or an easily eliminable group such as, for example Tosyl or mesyl group.

The reaction takes place advantageously in an inert oceanic Solvent instead, for example in chlorinated hydrocarbons such as chloroform or dichloromethane, in aromatic or aliphatic hydrocarbons such as benzene, toluene or petroleum ether, in alcohols such as methanol or Ethanol or in acetonitrile or its ether. The temperature is between the ambient temperature and the Reflux temperature of the reaction mixture. The reaction can be carried out with advantage in the presence of an organic base such as Pyridine, triethylamine or N, N-dimethylaniline, or an inorganic base such as the hydroxides, carbonates and bicarbonates the alkali or alkaline earth metals or finely powdered lime take place.

The alkylated derivative can also be reduced by reducing the corresponding acylated derivative can be obtained by classical methods.

The introduction of the substituent R ^ = CONH.- takes place in conventionally by reacting the derivative (VIII) with the isocyanate of an alkali metal or ammonia the scheme:

V, ^C0R 3 Rl for ₃

hl \ H.

(O) _n -S NH + MNCO * - (ο) .ς N-CONH.

^R 7 R ₆ R ₇ ^R 6 ^J

(VIII) (X)

ZZ

; 3 2 4 2 66 $

In this scheme, lip R ₂ , R? » R ₁ Z ₁ R ^ »

, and η the

meaning given above. M is a monovalent cation, for example a sodium, potassium, lithium or Ammonium ion.

The reaction takes place in the classical way in water at a temperature which is between normal temperature and the reflux temperature is.

The hydantoin (XI) is obtained by using the derivative; (X), in which R 1 represents a hydroxyl group, in one heated acidic aqueous solution.

1.COR ₃

(O) _n -S N-CONH ₂ -

R ₇ R ₆ -5

(X)

(XI).

In this diagram, Rx ,, R ~, R ,, R ^, Ii / -, R, ^ and η the meanings given above.

Zl

²⁸ - $ 224266

The acid used is an inorganic acid , for example a hydrohalic acid such as hydrochloric acid, hydrobromic acid, hydriodic acid or nitric acid, sulfuric acid or phosphoric acid.

The reaction mixture is generally at a temperature brought near the reflux temperature of the solution.

Transformation of the derivatives in which R-, the hydroxyl group is, in derivatives in which R, a group ORq, ü CHOOOi

or means OCH-OCOR ₁₁ is an esterification. The Ver-

Esterification of an acid is a general reaction that can take place in a number of ways. According to the classic method acid and alcohol in the presence of an acidic catalyst such as hydrochloric acid, sulfuric acid or p-To1uo.Tsulfonsäure brought to reaction. This reaction advantageously takes place under anhydrous conditions, and it becomes one the reactant used in large excess. The solvent can either from one of the reactants or from a neutral organic solvent, for example from chlorinated hydrocarbons such as chloroform or carbon tetrachloride or an aromatic or aliphatic hydrocarbons such as benzene, toluene or petroleum ether. The temperature is between <; er normal temperature and the reflux temperature of the reaction mixture

Another method is to distill off the water in its development using a suitable apparatus. The act ion conditions are the same as those described above, apart from the fact that one of the reaction partners is not used in large excess needs to become.

The hydrolysis of the ester takes place under the same conditions like the esterification, but in this case one of the reactants, optionally the water, has a very large Used excess. The catalytic conditions and the temperature are the same as for the esterification.

The transformation of the derivatives in which R ^ is a hydroxyl group or a group such as ORq ι OCHCOOiL »,, or

¹ IO

-OGO R ^ means in derivatives in which R * 10

/ 12
a group N means, in a classic reaction,

which is well described in (1 literature Several methods take place, which are described below

are.

For example, the carboxylic acid can be brought together with an amine will. The pyrolysis of the salt thus formed leads to the amide, as does the action of a dehydrating agent like Pp ^ 5

Another method is to convert the carboxylic acid into an acid halide and then by acting a :; To convert amine into the amide. The acid is often converted into the acid halide without a solvent by means of thionyl chloride, phosphorus pentachloride or phosphorus oxychloride. The corresponding bromides can also be used. To ensure a complete reaction, it is often useful to heat the reaction mixture to a temperature between 50 and 15O ⁰ G. If a solvent is useful for the reaction to take place, it will be a neutral organic solvent, for example hydrocarbons such as benzene, toluene or petroleum ether, or ethers such as diethyl ether.

The reaction between the acid halide and the amine takes place while cooling the reaction mixture to a Temperature between 0 ° and - 50 ° C, by stirring in one Excess of the amine (at least two equivalents or at least one equivalent of the amine and at least one Equivalent of a tertiary organic base, for example Triethylamine). In the classic way, the acid chloride is dissolved to the amine in a neutral organic Solvent, as indicated above, or also dissolved in water is added. Another method is to

to bring a carboxylic acid and an amine into reaction in the presence of a coupling agent, such as is used, for example, in peptide synthesis. There currently exist a large number of coupling agent such as dicyclohexylcarbodiimide, N-ethyl-N ^1, 5-dimethylaminopropyl, phosphines, phosphates, silicon tetrachloride, Tintantetrachlorid or EEDQ.

The ainolysis of an ester classically either occurs in water or in a neutral organic solvent. Examples of useful solvents can be aromatic ones Hydrocarbons such as benzene or toluene, aliphatic hydrocarbons such as hexane or petroleum ether, halogenated Name hydrocarbons like dichloromethane or chloroform.

The presence of a strong base can be essential in the case of a reaction with less basic or sterically hindered amines be. The above reaction can be carried out at a temperature between room temperature, and the RiiokfIußt; empora1; ur de; .i LÜ3ungsmibLeIs read.

Depending on the conditions used, the hydrolysis of an amine, i.e. a derivative in the R, can be a group

means to give a carboxylic acid or ester.

All of the methods described above allow one easy access to ile derivatives of 1,4-thiazaii the invention. The composition of the mixture obtained

however, it varies depending on diastereoisomers; the method used. The fractionation of these mixtures of diastereoisomers takes place according to the in organic chemistry classic way.

Some detailed examples of the preparation of some derivatives according to the invention are given below. The main purpose of these examples is to illustrate the particular characteristics of the method according to the invention.

Example 1; 2,2-Dimethyl-1,4-thiazane-3-carboxylic acid 1) S- (2-Hydroxyethyl-1-penicillamine

To a solution of 14.9 g (0.10 mol) of penicillamine in 75 ml of 2 η sodium hydroxide solution, which under a neutral atmosphere (Np) is kept dropwise and under vigorous Stir a solution of 17.5 U (0.14 mol) 2-bromoethanol added in 100 ml of ethanol. After the addition is complete, a sufficient amount of ethanol is added, to get a homogeneous mixture. The mixture is then stirred at ambient temperature for 24 hours. After neutralizing with concentrated hydrochloric acid, the bulk of the alcohol is evaporated under reduced pressure and the; Hest crowd up 300 ml filled up. The resulting solution is fixed in a resin column that is conditioned in the form of acid Resin of type Dowex 30 contained ;. Dan Harz win) mil.Wy:;:; ar

washed and then eluted with 3 liters of η-ammonia. The eluate is evaporated to dryness. 50 ml of water and 500 ml of ethanol are added to the residue. The solid is then filtered off and recrystallized from isopropanol. 0.0 g (4-7%) of a white plague are obtained in this way. F. ⁰

2) S- (2-chloroethyl) penicillinamine hydrochloride

A mixture of 9.0 g (47 mMl) of the previous product UDd 350 ml of 38% hydrochloric acid is heated for seven hours by means of a bath kept at 95.degree. It is evaporated to dryness under reduced pressure and the residue is recrystallized from isopropanol. 8.9 g (760έ) of the homogeneous product are obtained by thin-layer chromatography on silica (eluant: BuOH / AcOH / H ₂ O: 13: 3: 5) -Rf. 0.59.

3) 2,2-Dimethyl-1,4-thiazane-3-carboxylic acid

6.7 g (27 mmol) of the preceding chloride are dissolved in 450 ml of N, N-dimethylformamide and then add 50 ml of triethylamine before the mixture is heated in a bath kept at 95 ° C. for 2.5 hours. Then will evaporated to dryness under reduced pressure. The residue is dissolved in 75 ml of water and the solution Percolated over 250 ml of the Dowex 50 resin. Man

3242555

washes with water and then eluted with 1.5 liters of ammonia. The eluate is concentrated under reduced pressure to a volume of 400 ml. The resulting solution is then conditioned overnight with 100 l of the resin of the Amberlite IRC 50 type in the form of acid. After filtering off the resin, the solution is concentrated to a volume of 30 ml. The crystals that appear are filtered off and redissolved in 100 ml of water. The slow addition of 40 ml of acetone causes the end product to precipitate. Weight: 3.1 g (66%).
F. 32O ⁰ C (decomposition).

The I.E., MMR and mass spectra show agreement with the expected structure.

Elemental analysis: CH N

% calculated 48.0 7.5 8.0 % found 47.9 7-4 7-9

Example 2: 2,2,5- (R, S) -trimethyl-1,4-thiazane-3- (S) -carboxylic acid

1) S-All.-ylpenicillin amln

To a suspension of 7.5 g (50 mMl) penicillinamine in 50 ml of ethanol are slowly and simultaneously a Solution of 6.6.g (4.1 ml; 55 mMl) allyl bromide in 50 ral Ethanol and 35 ml of 2 η sodium hydroxide solution were added while

the temperature of the solution is kept below 20 ° C. After the addition is complete, the mixture is stirred for a further 2 hours and the disappearance of the starting thiol monitored (silica thin film ; Eluent BuOH / AcO / I ^ O 12: 3: 5; Visualization with Winhydrin).

The solution is neutralized using concentrated hydrochloric acid and then concentrated until a solid appears. It is made up to 300 ml with water, and the solution obtained is percolated over a sulphonic resin column (Amberlite IR 120) which is conditioned in the form of acid. The resin is washed with water and eluted with 111N ammonia. The eluate is evaporated to dryness and the solid residue is recrystallized from isopropanol. 7.8 g (82%) of the product are obtained in this way. F. 182-184 ⁰ C.

2) S- (2-bromopropyl) penicillamine bromine hydrate

The product from the previous step (7 »8 g; 41 mmol) is added with stirring to 300 ml of a solution of 40% hydrobromic acid in acetic acid. After stirring for 3 hours, the reaction mixture is evaporated to dryness under reduced pressure. The residue is then stirred into ether and filtered off. The solid residue is used unchanged for the next step. Weight: 14.2 g (99%).
F. 106-108 ⁰ C.

3) 2,2,5-trimeth.yl-i ^ -thiazan - ^ - carboxylic acid

The previous product (14.2 g; 40 mmol) is added to 500 ml of DMF which reveals 50 ml of triethylamine. The mixture is heated for 2.5 h in a ^{water bath kept at 90 °} C. and then evaporated to dryness under reduced pressure. The residue is dissolved in 400 ml of water and the solution is perculated over 500 g of an acid-conditioned sulfonic resin (Amberlite IR 120). The resin is washed with 2 liters of water and then eluted with 2 liters of ammonia. The eluate is evaporated to dryness under reduced pressure. The residue is dissolved in 500 ml of water and mixed with 50 ml of Carboxylharζ (Amberlite IRC 50), which was conditioned in the form of the acid. After filtering, the aqueous phase is evaporated to dryness under reduced pressure. The residue is dissolved in 50 ml of a mixture of acetone and water in a ratio of 2: 1 and the solution is placed in the refrigerator. After 5 days, the crystals which have appeared are observed. After washing with acetone and drying, the following is obtained: 3.7 g (45%) of the product.
F.29O ⁰ C (decomposition).

The IR, -MMR and mass spectra confirm the structure of the cyclized product.

The Karl Fischer analysis shows the presence of 8.7%

Water.

Elemental analysis: C H .N

° '° calculated 46.4 8.3 6.8 % found 46.1 8.5 6.4

In an investigation by thin-layer chromatography on silica and elution using a mixture of butanol / Acetic acid / water in the ratio 2: 3 = 5, the product appears homogeneous. After a sililation, however, the Chromatography in the vapor phase indicates the presence of two epimers in equal proportions.

Example 3: 1-Rjβ) -oxy-2,2,5- (S) -trimethyl-1,4-thiazane-3- (S) -carboxylic acid

The mother liquors from the recrystallization and the washing acetone from the previous example were carefully saved and are now evaporated to dryness under reduced pressure. The solid, white residue is recrystallized from ethyl acetate. The resulting solid is then finely ground in acetone and then recrystallized from a mixture of acetone and water. In this way 0.75 g (7% in relation to the bromohydrate of S (2-bromopropyl) -penicillamine) of 2,2,5- (S) -trimethy1-1,4-thiazan-3- (S) -carboxylic acid, enriched to 98%.
F. 328 ⁰ C (decomposition)
E) CJ ²⁰ = 1 $ 1 ^O (C = 0.5; water).
^D.

Elemental analysis: CH N

calculated 50.8 7.8 7.4 % found: 50.5 8.0 7.7

The above sulfate is dissolved in 10 ml of acetic acid, to which 0.4 ml of JO% hydrogen peroxide is added. The mixture is stirred at ambient temperature for 24 hours and then concentrated under reduced pressure until a syrup is obtained. Then 25 ml of acetone are added and the mixture is stored at 5 ° C. overnight. The crystalline solid is then filtered off and dissolved in 10 ml of water. Concentrate the solution until a syrup is obtained. This treatment is repeated and then gives 0.29 g (47% of a white solid, which consists of a mixture of two epimeric sulfoxides. F. 250 ^° C. (decomposition)

The IR, NMR and mass spectra are consistent with the expected Structure. The Karl Fischer analysis shows the presence of 2.2% water.

Elemental analysis: CHN

calculated 45 ,8th 7th , 5 .6 , 7 found 45 , 6 7th , 4 6th , 9

Example 4: 2,2,5- (R) -trimethyl-1,4-thiazane-3- (S) -carboxylic acid

3.25 ml (40.3 mmol) of freshly redistilled chloroacetone are added to a suspension of 5 g (33 »6 mmol) of D-penicillamine in 28 ml of water, while stirring. When the mixture has become homogeneous, the reaction vessel is immersed in an ice bath. Is then added dropwise a 20% sodium hydroxide solution, until a pH5,3 achieved without the temperature exceeding 10 ⁰ C. Then a solution of 1 g (26.4 mMl) of sodium borohydride in 5 ml basified water is also added dropwise, so that the temperature does not exceed 30 ⁰ C, is added. After the addition, the mixture is stirred for a further hour at ambient temperature * 37% hydrochloric acid is then slowly added until a pH of 5.0 is reached. The mixture obtained is then evaporated to dryness under reduced pressure and the residue is taken up in 50 ml of absolute ethanol. The insoluble is filtered off and the filtrate is evaporated to dryness under reduced pressure. The remaining colorless oil is redissolved in 10 ml of water. It is evaporated to dryness under reduced pressure. The resulting white solid is mixed with 10 ml of water and the mixture is refluxed until dissolved. The solution is allowed to crystallize by standing at ambient temperature for 4 hours and then at 5 ° C. overnight. .Dex ^ solid is filtered off and dried. Weight: 4.3 g (20.7 mmol; 72%).
F. 310 ⁰ C (decomposition) ./.

²⁰ = ₊ 93 ° (C = 1; water) D.

The Karl Fischer analysis shows the presence of 8.7% Water on.

The IR, JNMR, and mass spectra are as expected Structure in accordance. The HPLC analysis proves the Homogeneity of the end product.

Elemental analysis: CH N

calculated 46, 4- 8th, 3 6th , 0 found 4-6, 3 8th, 3 6th , 9

According to thin-layer chromatography on silica, the product has an R ™ of 0.69 after elution with a mixture from methanol, acetic acid and chloroform in the ratio (: 1

Example 5'- 1- (R) -oxy-2,2,5- (R) -trimethyl-1,4-thiazan-3- (carboxylic acid

Men prepares a solution of 5.5 K (16.7 mMl) of the Froduki.cfi of the previous example in V / ml of a mixture of acetic acid and water in a ratio of 1: 1 and cools it down in an ice bath. Then , dropwise and with stirring, 1.94 ml of 30% hydrogen peroxide are added over the course of 5 minutes. After the addition, the mixture is stirred for 8 hours, maintaining the cooling bath, and then for 10 hours at ambient temperature. It is evaporated to dryness under reduced pressure at a temperature not exceeding 60 ° C. The oily one

The residue is dissolved in 10 ml of water and the solution is evaporated to dryness under reduced pressure. Repeat this operation until a solid is obtained. This is then dissolved in 6 ml of water. 15 ml of acetone are slowly added with stirring. The mixture is stirred for 1 hour at ambient temperature and filtered off. In this way a first amount of the desired sulfoxide is obtained. A second amount is obtained by ^{cooling the mother liquors to 10 °} C., adding 10 ml of acetone to them and then filtering off after a crystallization time of 15 minutes. Total weight: 2.2 g (9.9 mmol; 59%). F. 246 ⁰ C (decomposition)

τ 20

l & Q. _ 3.5 ° (C = 1; InHCl). D.

The IR-NMR and mass spectra show agreement with the expected structure.

The analysis of the corresponding hydrochloride means X-rays allow to confirm the absolute structure.

Karl Fischer analysis shows the presence of 8.2% Water on.

Elemental analysis: CH N

% calculated 43.0 7.7 6.3% found 43.2 7.6 6.4

Examination using a thin layer of silica shows that the product after elution with a Mixture of ethanol, acetic acid and chloroform in the ratio 6: 1: 4 has a Bj of 0.42.

The HPLC analysis confirms the homogeneity of the product.

Example 6; 2,2,5- (R) -trimethyl-1,4-thiazane-3-3 (S) - ^Λ carboxylic acid hydrochloride

The mother liquors from the crystallization of the second batch of the previous example, carefully preserved , are evaporated to dryness under reduced pressure. The residue, which weighs 1.3 g, is brought to pH 1 in 10 ml of water. The solution is concentrated until a moist mass of 3.0 g is obtained and the residue is kept at 5 ° C. overnight. The pest is filtered off, which has a rotation capacity of 79 ° in water. The crystals are dissolved in 10 ml of water and evaporated under reduced pressure until a syrup is obtained. It adds 1.5 ml acetone and raises the mixture overnight at 5 ° C. Then it is filtered. The rotation of the solid is 84 °. A further crystallization step provides a product of sufficient purity. Weight: 0.22 g (0.9 5% in relation to the product used in Example 4).

M.p. 275 ° C

²⁰ - + 85 ° - (C-1; WasL,.: R), + 73 ° (C »1; In-HCl). D.

The IR, NMR and mass spectra are consistent with the expected structure.

The Karl Fischer analysis shows the presence of 0.5% Water on.

Elemental analysis: CH N

% calculated 39.8 6.7 5.8% found 39.8 6.7 5.9

The HPLC analysis shows a purity of 99.5%

Example?: 1, i-dioxo-2,2,5- (R) -trimethyl-1,4-thiazane-3- (S) -carboxylic acid

5 g (22.4 mmol) of the product from Example 5 are dissolved in 300 ml of 0.5 η-sulfuric acid. A solution of 2.5 g of potassium permanganate is then added to 300 ml of water over the course of 2 hours. When the addition is complete, ⁿ wi rd stirred for 2 h at ambient temperature. Then 12 ml of formic acid are added. It is filtered and then an aqueous, 0.5 η solution of barium hydroxide is added until the precipitation has ended. It is filtered and the filtrate is passed through a column of ion exchange resin of the strongly acidic type which has been conditioned in the form of H ^. Mix the resin until the rinse water is neutral and then elute with ammonia. The eluate is concentrated while reducing the pressure to a volume of about 100 ml. The solution of the resulting ammonium salt is then percolated over a resin column of the weakly acidic type. Dar, filtrate will

evaporated under reduced pressure until a syrup is obtained, to which 15 ml of acetone are added. The mixture is stirred for 2 hours and filtered. Weight: 2.7 g (11.6 mmol; 52%). F: 232 ⁰ C (decomposition).

COO} ²⁰ = + 2 ° (C = 1; 1n HCl). D.

The IR-NMR and mass spectra agree with the expected Structure.

The Karl Fischer analysis shows cImg existence of (■>, <', ■ <' Water.

Elemental analysis: CHN

calculated 40 , 7 7, 1 5 , ^ found 40 , 7 7, 5 5 , 9

The investigation in a rock thin r.cl:J c.ht shows that the product, after elution with a mixture of butanol, acetic acid and water in a ratio of 5 ^: 2: -5, has an H “of 0.8 owns.

Example 8: 5- ^m ethyl-1, 'l-thiazan - ^ - carboxylic acid hydanto Ln

Successively 5.9 g (24.0 mmol) of 5-methyl-1,4-thiazane-3-carboxylic acid and 2.3 g (28.8 mmol) of potassium isocyanate are added to 25 ml of water. The mixture is heated to a boil and then returned to ambient temperature. The solution of 5-n- ^i- ethy] - ^/ i-ureido-1, -'-(-thiazane-3-carboxylic acid obtained in this way is then mixed with 54 ml of 10% acid

^: ■ "·:.." ·: ■ ".: 3242565

offset. The mixture is then concentrated under reduced pressure to a volume of 20 ml. The mixture is then stirred for 1 hour at ambient temperature and then filtered. The solid is finally recrystallized in water. Weight: 2.5 g (13.4 mmol; 56%).
F. 189 ^C C (decomposition)

The IR, NMR and mass spectra agree with the expected Structure.

Elemental analysis: CH N

% calculated 45.2 5.4 15.O % found 44.9 5.5 15.1

Example 9 1-ethoxycarbonylethyl ester of 1 ~ oxo-2,2,5-trimethyl-1,4-thiazane-3-carboxylic acid (oxalate)

A solution of 3.7 g of 07 »4 mMl) of the product according to the example 5 in 37 ml of water is mixed with a solution of 0.5 N kale! added until the pH reaches 9. The resulting solution is used under reduced pressure Evaporated dry. The residue is suspended in 40 ml of DMF. Then 3.2 g (17.6 mmol) are added dropwise of the ethyl ester of 2-bromopropionic acid was added. The mixture is stirred for 48 hours at ambient temperature and then diluted with 100 ml of water before being extracted with chloroform. The organic extract is dried and then under reduced pressure to dryness

The residual oil is taken up in 50 ml of ethanol and then treated with a solution of 1.6 g (17 _f 6 mmol) of oxalic acid in a minimum of the same solvent. The mixture is stirred for 30 minutes and filtered. The solid obtained in this way is recrystallized from ethanol. 4.3 g (10.5 64%) of the pure product are obtained.
F. 196 ⁰ C (decomposition)

The IR-NMR and mass spectra are consistent with the expected structure.

The Karl Fischer analysis shows the presence of 3.1% Water on.

Elemental analysis: C H N

% calculated 44 * 1 6.5 3.4 % found 44.1 6.7 3.3

Chromatography in a thin layer of silica yields after elution with a mixture of butanol and acetic acid and water a ratio of 5: 2: 3 that the product is one of 0.52.

Example 10: Pivaloyloxyethyl ester of 1-oxo-2,2,5-

trimethyl-1, ^ - thiazane-3-carboxylic acid (oxalate)

A solution of 3.7 g (16.4 mmol) of the product according to Example 5 in 37 ml of water is mixed with a 0.5 η potassium hydroxide solution until the pH reaches a value of 9. The resulting solution is evaporated to dryness under reduced pressure. The residue is suspended in 40 ml of DMF. 2.9 g (17.6 mmol) of 1-chloroethyl pivalate are added dropwise with vigorous stirring. After the addition is complete, stirring is ^{continued at 40 °} C. for 48 h. The resulting liquid is diluted with 100 ml of water and then extracted with chloroform. The organic extract is dried and then evaporated to dryness under reduced pressure. The residue is mixed with 50 ml of ethanol and then with a solution of 1.6 g (17.6 mmol) of oxalic acid in a minimum of the same solvent. The mixture is stirred for 30 minutes and then the precipitate formed is filtered off. This is finally cleaned up by recrystallization in ethanol. 4.2 g (9.9 mmol; 60%) of white crystals are obtained.
F. 214 ⁰ C (decomposition)

The IR, NMR and mass spectra agree with the expected Structure.

Elemental analysis: CHN

% calculated 48.2 6.9 3.3% found 48.1 7.2 3.2

te

Chromatography in a thin layer of silica shows that after elution using a mixture of butanol, Acetic acid and water in a ratio of 5: 2: 5 the product Rj, of 0.65.

Example 11: 2,2,5-trimethyl-1,4-thiazane-3-carboxylic acid methyl ester (hydrochloride)

A solution of 52.2 g of potassium hydroxide in 640 ral methanol is cooled to 0 to 5 ° C. 47.9 K (0.24 MoJ) penicillamine methyl ester chlorohydride and then 25.0 g of chloroacetone are added dropwise. The mixture is stirred for 1 hour at the starting temperature and the solution is then brought to a pH of 6.5 using a hydrochloric acid-ethanol mixture. Small amounts of 6.2 g of sodium borohydride are then added. After the addition is complete, the mixture is stirred for a further hour, always at the same temperature. The excess hydride is destroyed by adding concentrated hydrochloric acid. The solution is then neutralized with 10% carbon dioxide. The aqueous solution is extracted with chloroform. The extract is dried and then evaporated to dryness under reduced pressure. The residual oil is dissolved in a mixture of 50 ml of methanol and 350 ml of ether. The addition of hydrochloric acid in a saturated solution in ether causes the solid hydrochloride to precipitate. This is filtered off and reprecipitated twice after dissolving in methanol by adding ether.
Weight: 17.2 g (30%)
F. 204 ⁰ C (decomposition).

The IR, NMR and mass spectra are consistent with the expected structure.

Elemental analysis: CHN

% calculated 4-5.1 7.6 5.8 % found 45.1 7.7 5.8

Example 12; 2,2,4,5-tetramethyl-1,4-thiazane-3-5-carboxylic acid

1.68 g (20 mmol) of sodium bicarbonate and 1.5 g (0.66 ml; 10.5 mmol) of methylsodide are added successively to a solution of 2.1 g (10 mmol) of 2,2,5-trimethy1- 1,4-thiazane-3-carboxylic acid in 50 ml of methanol was added. The resulting liquid is stirred at ambient temperature for 24 hours and then the amount is brought to reflux temperature for the same time. It is evaporated to dryness under reduced pressure and the residue is taken up in 100 ml of water. The solution thus obtained is passed through a column of ion exchange resin of the strongly acidic type which has been conditioned in the form of H ^. The resin is washed with water until the effluent is neutral. Then it is eluted with 1N ammonia. The eluate is evaporated to dryness under reduced pressure. The remaining white solids are recrystallized from ethyl acetate. In this way 1.4 g (6.8 mmol; 68%) of the pure product are obtained.
F. 201 ⁰ C (decomposition)

is-

The IR-NMR and mass spectra agree with the expected Structure.

Elemental analysis: C H N

% calculated 53.2 8.4 6.9

% found 52.8 8.5 7.0

Chromatography in a thin layer of silica shows that the product
0.60.

that the product has an R ™ of after elution with methanol

Example 13: 5-n-butyl-2,2-dimethyl-1,4-thiazane-3-carboxylic acid hydrochloride

7.5 g (50 mMl) D-penicillinamine are added to 40 ml of water which is kept at a temperature between 0 and 5 ^° C. With vigorous stirring, on the one hand 9.5 g (53 mMl) 1-bromo-2-hexanone are added dropwise and simultaneously over the course of about 10 minutes and on the other hand 25 ml (50 mMl) 2N sodium hydroxide solution over the course of about 30 minutes. After the addition is complete, stirring is continued for about a further hour while maintaining the temperature, after which the temperature is adjusted to about 15 ° C. 50 ml of methanol are added and then slowly a solution of 1.5 g (39 mmol) of sodium borohydride in 9 ml of water that has been made basic. The mixture is allowed to return to ambient temperature and extracted with pyroform. The organic extract is dried and then evaporated to dryness under reduced pressure. The residual red oil is taken up in 50 ml of di-isopropyl ether, to which sufficient ethanol is added to obtain a solution. Ether chlorohydride is then added / .u until the precipitation has ended int, and then p; enüp; end

ethanol to turn the red-brown mass into a beige To form pesticide. It is filtered, washed with diisopropyl ether and dissolved in ethanol while warm. Ethyl ether is added until a permanent cloudiness appears and leave to cool. The crystals are separated off and a second is cleaned Times.

Weight: 8.0 g (30 mmol; 60%) F. 225 ° G (decomposition)

The XW, NMR and Masa spectra agree with the expected Structure.

Elemental analysis: CHN

% calculated -4-9.3 8.3 5.2 % found 49.5 8.2 5.5

Chromatography in a thin layer of silica shows after elution after mixing with butanol, acetic acid and water in a ratio of 5: 2: 3 that the product has a fi _p of 0.62.

Example 14-: 5-diethyl-2-phenyl-1,4-thiazane-3-carboxylic acid hydrochloride

Dissolve 1 g (4.3 mmol) of the hydrochloride of trio-ß-phenylcysteine in 12 ml of water. The solution is cooled in an ice bath

- MT-

and then brings it to a pH of 7.0 using 20% sodium hydroxide solution. 0.42 g ( ¹ l, ') mMl) freshly redeemed 1J ertes chloroacetone is added. After the pH has stabilized for 30 minutes, 2N sodium hydroxide solution is added until neutralization. The mixture is stirred for a further 1 h, still in an ice bath, and then a solution of 0.13 g (3.4 niMl) of sodium borohydride in 2 ml of water that has been made basic is added. A colorless and clear solution with a pH of 9.1 is obtained. The mixture is stirred for 1 hour and the solution is allowed to come to ambient temperature. The pH is brought to 6.0 using 37% hydrochloric acid. It is evaporated to dryness under reduced pressure. The sufficiently dried residue is taken up in 10 ml of ethanol, to which 2 ml of 22% hydrochloric acid in ElhanoJ are added. The mixture is stirred for 1 1/2 minutes and then evaporated to dryness under reduced pressure. The residue is recrystallized twice in a mixture of isopropanol and ethanol in a ratio of 4: 1. ·

Weight: 0.66 g (2.4 mmol; 56%).
F. 248 ⁰ C (decomposition).

The IR, MNR and mass spectra agree with the expected el.en structure.

Elemental analysis:

b ere c hu ot, C. 5? , 6 H N 1 % found 3 1
- 1 % 's

Example 15: 1- (R) -oxo-2,2,5- (R) -trimethyl-1,4-thiazan-3-

(S) -carboxylic acid (without isolation of intermediates)

7.4 g (80 mmol) of freshly distilled chloroacetone are added to a suspension of 10 g (67 mmol) of (D) -penicillamine in 56 ml of water at ambient temperature with vigorous stirring. After 2 h reaction time 20 / o Watronlauge is to reach a pH 5 »3 added (temperature <20 ⁰ C). A solution of 2 g (50 mMl) sodium hydroxide in TO ml of water is added dropwise to the reaction mixture (temperature ^ 30 ⁰ C). After a reaction time of 1 hour, the solution is acidified by adding 50 ml of acetic acid. The reaction mixture is cooled to a temperature between 0 and 5 ° C. and 2.4 g (0.74 mol) of 30% strength hydrogen peroxide are added dropwise. The temperature is maintained for 8 h between 0 and 5 ° C and then for 4 h at 20 ⁰ C.

Concentrate under reduced pressure. The residue is taken up in 40 ml of ethanol, the suspension is filtered and 250 ml of ethyl acetate are added to the ethanol solution while stirring vigorously. It is allowed to ^{crystallize at 20 °} C. for 1 h. The crude amino acid is recrystallized in a mixture of water and acetone in a ratio of 1: 4. You get; so 7.4 g (33.3 mmol; 54%) of white crystals which are identical to the products of Example 5.

The following Table I is a compilation of the derivatives according to the above examples and further derivatives according to the invention, which are prepared by the above process; have been.

TABLE I.

N ° ^R l R ₂ ^R 3 ^R 4 NH-CO OCH ₃ H NH-CO OH H ^R 5 ^R 6 ^R 7 η F ⁰ C (I) Solvents of the >
Recrystallization 1 CH ₃ CH ₃ OH H OH H OCH ₃
OH
OH H
H
H H H H 0 320 (5th Jlceton / Vasser 2 CH ₃ CH ₃ OH H OH H H H H 1 242 (3) Isopropanol / water 3 CH ₃ - CH ₃ OH H CH ₃ H H 0 290 (3) Acetone / water (7) 4th CH ₃ CH ₃ OH H CH ₃ H H 1 190 (3.4 .Acetone / Water (7) 5 H H CH ₃ H H 0 189 (5) Water ί 6th CH ₃ CH ₃ CH ₃ H H 0 204 (4) Methanol / ether 7th CH ₃ CH ₃ CH ₃ H H 1 220 (3.4) Acetone / water (8) 8th CH ₃ CH ₃ CH ₃ H H 0 127 (5) water 9 CH ₃ CH ₃ CH ₃ H H 1 275 (3.4) Acetone / water (9) 10
11th
12th CH ₃
CH ₃
CH ₃ CH ₃
CH ₃
CH ₃ CH ₃
CH ₃
CH ₃ H
H
H H
H
H 1
2
1 107 (5)
23 2 (3.5)
246 (3.5) Diisopropyl ether
Acetone / water
.Acetcn / water (1C " 13th CH ₃ CH ₃ CH ₃ ^H 3 H 2. 256 (3.5) Water .

cn ■ cn

TABLE I.

N ^{0 R} l R ₂ ^R 3 ^R 4 ^R 5 ^R 6 ^R 7 η F-C (I) ^ -Solvent the
Mkri st alii sation (2 14th CH ₃ CH ₃ OH H CH ₃ H .H 0 328 (5th Acetone / water (11) 15th CH ₃ CH ₃ OH H CH ₃ H H 1 230 (3.5) Acetone / water (12) 16 CH ₃ CH ₃ 0-nC ₄ H ₉ H CH ₃ H H 0 176 (4) Methanol / ether 17th CH ₃ CH ₃ OH H CH ₃ CH ₃ H 1 271 (5) Acetone / water 18th CH ₃ CH ₃ OC ₂ H ₅ H CH ₃ H H 1 244 (4) Ethanol / ether 19th CH ₃ CH ₃ . 0-nC ₄ H ₉ H CH ₃ H H 1 235 (4) Methanol / ether 20th CH ₃ CH ₃ 0-n.CgH ₁₇ H CH ₃ H H 1 222 (4) Isopropanol 21 CH ₃ ^CH 3. OC ₂ H ₅ CH ₃ CH ₃ H H 1 184 (4) Isopropanol 22nd CH ₃ CH ₃ -0-pht H CH ₃ H H 1 220 (3.4) Ethanol (13) 23 CH ₃ CH ₃ OCHC ₁₀ H ₂₁
CH ₃ H CH ₃ H H 1 208 (4) Isopropanol 24 CH ₃ CH ₃ OCH ₂ CO ₂ C ₂ H ₅ H CH ₃ H H 1 200 (4) Isopropanol / ether 25th CH ₃ CH ₃ OH CH ₃ CH ₃ H H' 0 200 (5) Ethyl acetate

TAB3LL5 I

N ° ^R l R ₂ ^R 3 ^R 4 H ^R 5 ^R 6 ^R 7 η F ⁰ C (I) Solvent of
Itocrystallization ■ 26th CH ₃ CH ₃ OCHOCOtJC ₄ H ₉ H H CH ₃ H .H 1 214 (6 «Ethanol CH ₃ H 27 CH ₃ CH ₃ OCH ₂ CO ₂ MC ₃ H ₁₇ H H CH ₃ H H 1 159 (4th Isooctane 28 CH ₃ CH ₃ OCHCO ₀ C ₀ Hr
I ά C D
CH ₃ ZC H CH ₃ H H 1 196 (6 Ethanol 29 - (CH 2) 4- OH H CH ₃ H H O 273 (5) Acetone / water 30th CH ₃ CH ₃ OH COCH ₃ HC ₄ H ₉ H H O 225 (4) Ethanol / ether 31 CH ₃ CH ₃ OH HC ₄ H ₉ H H 1 173 (3) Acetone / water / water 32 CH ₃ CH ₃ OCH-pyr.
CH ₃ CH ₃ H H 1 203 (6) Ethanol (14) 33 CH ₃ CH ₃ OCH ₂ CO ^ ₄ H ₉ CH ₃ H H 1 215 (6) ■ ethanol 34 CH ₃ CH ₃ OCH ₂ CO ₂ C ₁₂ H ₂₅ CH ₃ H H 1 166 (6; Ethanol 35 CH ₃ CH ₃ OH CH-, H H O 149 (5] Stylacetate / hexane '

TABLE I.

N ° ^R l - (C R ₂ ^R 3 ^R 4 ^R 5 ^R 6 ^R 7 η F ⁰ C (I) solvent the
^ crystallization .. 36 CH ₃ ^C 6 ^H 5 I. CH ₃ OH H H H gem-
(CH ₃ ) 0 290 (5) Ethanol 37 CH ₃ CH ₃ OH H CH ₂ CO ₂ C ₂ H ₅ H H 0 205 (4) Isopropanol 38 ^CH 3 CH ₃ OH H 1.C ₃ H ₇ H H 0 247 (18 Isopropanol 39 CH ₃ CH ₃ OH H CH ₃ H H 0 310 (3rd '' Acetone / water (15 40 CH ₃ CH ₃ OH H CH ₃ H H 1 250 (3 Acetone / water (16 41 CH ₃ CH ₃ OH CHO CH ₃ H H 0 172 (5) Acetonitrile 42 CH ₃ CH ₃ OH H ^C 6 ^H 5 H H 0 232 (5) Isopropanol 43 CH ₃ CH ₃ OH H CH ₂ CO ₂ H H H 0 260 (3.5) water 44 CH ₃ CH ₃ OH H CH ₃ H H 0 310 (3) Acetone / water (17) 45 CH ₃ CH ₃ OH H H H CH ₃ 0 210 (4) Ethyl acetate 46 H ₂ ) ₅ - OH H CH ₃ H H 0 231 (3.5) Acetone / water 47 H OH H CH ₃ H H 0 248 (4) Isopropanol / ?,
Ethanol

TABLE I.

N ° ^R l R ₂ I ^CH 3 CH ₃ ^R 3 R ₄ ^R 5 ^R 6 ^R 7 η F ⁰ C (I) Solvent of
Recrystallization 48 - (CH ₂ ) ₂ -S- (CH ₂ ) ₂ - - (CH ₂ ) ₂ -0- (CH ₂ ) ₂ - CH ₃ OH H CHg H H 0 266 (3) water 49 CH ₃ CH ₃ CH ₃ OH CO (CH ₂ J ₂ CH ₃ CHg H H 0 101 (5) • Diisopropyl ether 50 CH ₃ H OH H CH ₃ H H 0 275 (3) water 51 CHg NH-CH ₂ -CH (Og) ₂ COCH ₃ CHg H H 0 - (5) oil 52 H H OC ₂ H ₅ H CHg H H 0 205 (4) Ethanol / ether 53 H OC ₂ H ₅ COCH ₃ CHg H H 0 V (5) oil fco.- 120-130 ⁰ C /
■ 2.10-3 torr. 54 H OCHCO ₂ C ₂ H ₅ H CHg H H 1 170 (6) Ethanol H I LL iJ
CH ₃ 55 OH CHg CHg H H 0 198 (5) Isopropanol / ethyl ^s -
ac et at 56 OCH ₂ CO ₂ OC ₈ H ₁₇ H CH ₃ H H 0 - (5) Cl

co. cn

.AO ^ Juix- ·. ·· -. 1.

N ° ^R l - CH ₃ CH ₃ C. CH ₃ R ₂ CH ₃ ^R 3 ^R 4 ^R 5 H ^R 7 η F ⁰ C (I) Solvent of
Recrystallization 57 H - (CH ₂ J ₂ -! CH ₃ CH ₃ H CH ₃ OCHCO ₂ C ₂ H ₅
CH, H CH ₃ H H 0 - (5) • oil 58 CH ₃ Cf CH ₃ CH ₃ CH ₃ j
OH COCH (CH ₃ ) CH ₃ H H 0 129 (5) Cyclohexane 59 CH ₃ -H ₂ J ₅ CH ₃ OH H CH ₃ H H 0 259 (5.3) Ethyl acetate 60 CH ₃ <- (CH ₂ ) ₂ - NH-CH ₂ -CH (CH ^ H CH ₃ H H 0 141 (5th Cyclohexane 61
62 H
M- (CH ₂ ) ₂ - ^{: H} 2 " ^C 6 ^H 5 OH
OH H
H C-) O
rc rc
CO OO H
H rc rc 0
0 298 (5th
235 (5th Isopropanol / water /
acetone
Ethanol ^! 3 CH ₃ 63 CH ₃ OH TC ₄ H ₉ CH ₃ H H 0 217 (4) acetone 64 OH H H H HC ₄ H ₉ 0 240 (5) Ethyl ac et at 65 OH HC ₄ H ₉ CH ₃ H H 0 246 (4) Ethyl acetate 66 OH H IT-C ₆ H ₁₃ H H 0 205 (4) "Methanol / ether 67 OH H CH ₃ H H 0 242 (4) Ethanol / ether 68 NH ₂ H CH ₃ H H 0 112 (5th Cyclohexane 69 N (C ₂ H ₅ J ₂ H CH ₃ H H 0 181 (4) Isopropanol / ether

CJ IS)

(1): It is mostly the decomposition temperature. The specified value corresponds to the beginning of this Appearance.

(2): All the products mentioned give a correct elemental analysis CHN.

(3): hydrated product.

(4): hydrochloride.

(5): Free base or zwitterion.

(6): oxalate.

(7) i Mixture of isomers, the components of which appear separately from one another in the table below.

(8): Configuration of the asymmetry centers: 1- (R) .3- (S) -5- (R)

(9): Configuration of the asymmetry centers: 1- (S) -3- (3) -5- (R) (10): Configuration of the asymmetry centers: 1- (R) -3-G ->) - 5- (R) (11): Configuration of the asymmetry centers: 3- (S) -5 - (^) - (12): Configuration of the asymmetry centers: 1- (R, 3) -3- (S) -5- ('

(13): pht means 3-phthalidyl.

(14): pyr means 2,5-dioxo-1-pyrrolidinyl.

(15): Configuration of the asymmetry centers: 3- (K) -5 - (^) (16): Configuration of the asymmetry centers: 1- (3) -3- (R) -5 - ("/ (17): Configuration of the asylum centers: 3- (o) -! 3- (R).

(18): hemi-hydrochloride.

The products of the invention have become a series of pharmacological Subject to tests. The methods used are described below. The results these tests are summarized in Table II, in which the numbers in the 1st column correspond to the numbers in the 1st column correspond to Table I.

The DL50 were made according to the method of Lichtfield and

Wilcoxon (J. Pharmacol. Exp. Ther. £ 6.99, 19W calculated and are given in mg / kg. The products were administered to mice by the oral route.

The effect on behavior was examined using a method derived from the method of S. Irwin (Gordon Res. Conf. On Medicinal CIiem., 133 «1959). The substances, suspended in a 1% adragant gum mucus, were administered orally to groups of 5 male mice (strain CD1, Charles River, fasted for 18 hours) by means of an intergastreal tube. The doses administered as a function of the activity observed ranged from 3000 to 3 mg / kg. The behavior was examined 2, 4, 6 and 24 hours after the treatment. The observation was extended if symptoms were still present at the time. Mortality was recorded during the 14 days following treatment. None of the tested products caused abnormal behavior in the mice, nor were they found to be toxic.

TABLE 2

Pharmacological results

N ° ^DL 50 Fi "brinoly
1 h table effect
3 h " Bleeding!
1 h 3duration
"3 h Blood butt?
1 h ~ imtrerlust
3 h 1 5 7th 6th 2 4th 6th 5 3 7th 5 7th 6th 7th 5 4th > 3000 9 9 8th 6th 5 5 5 6th 6th 4th 5 5 4th 6th > 1000 6th (Jl 8th 3 9 4th 7th > 1000 9 6th 9 6th 9 7th 8th 6th 6th 4th 7th 5 8th 9 > 3000 5 9 4th 5 4th 4th 10 > 3000 7th 4th 7th 4th 5 5 11th 5 6th 4th 7th 5 7th 12th > 3000 7th 9 8th 9 6th 6th 13th > 3000 5 5 6th 5 5 6th 14th 5 4th . 5

NO CD CD

TABLE II

Pharmacological results

N ^{0 DL} 50 Fibrinoli
lh table effect
3 h i bleeding
lh duration
Yh Blood Gesar
1 h at loss
3 h 15th 7th 6th 4th 7th 4th 5 16 > 1000 5 5 7th 4th 7th 4th 17th > 1000 6th 5 8th 5 8th 7th 18th > 1000 5 9 4th 9 6th 9 19th 2600 7th 6th 7th 4th 8th 3 20th > 3000 6th 4th 6th 4th 5 5 21 6th 7th 9 4th 9 4th 22nd > 3000 4th 5 4th 5 6th 5 23 7th 4th 4th 9 4th 6th 24 > 3000 5 4th 4th 9 4th 5 25th 9 9 6th 5 7th 5 26th > 1000 7th 9 5 9 9 9 27 > 3000 5 8th 7th 9 6th 5 28 1900 7th 9 5 9 3 8th

• t C

TABLE II

Pharmacological results

N ° ^DL 50 Fibrinol
1 h iti effect
3 h Bleeding.
1 h duration
3 η Blood Ge si
1 h «Nt loss
3 h 29 5 5 7th 6th 6th 4th 30th > 1000 6th 9 3 9 4th 9 31 5 6th 4th 6th 4th 5 32 > 1000 5 4th 4th 5 4th 4th 33 > 1000 7th 5 4th 4th 4th 6th 34 > 1000 7th 6th 5 7th 5 9 35 > 3000 5 4th 3 5 5 5 36 6th 6th 7th 8th 9 5 37 > 3000 8th 8th 4th 7th 6th 9 38 9 9 5 Q 4th 7th 39 5. 6th 4th 4th 4th 4th 40 8th 6th 5 5 5 ς 41 > 1000 9 5 6th C. 5 4th 42 8th 5 6th 5 9

IABKlL-c Il

Pharmacological results

N ° ^DL «; n Pibrinolitic effect 3 h Bleeding duration 3 h Total blood loss 3 h bU 1 h 5 Γ h 5 1 h 3 43 5 5 5 4th 3 4th 44 9 7th 6th 6th 3 6th 45 5 4th 5 8th 5 7th 46 9 4th 5 47 4th 5. 9 48 4th 6th 9 49

Determination of the effect on the fibrinolytic activity by means of the bleeding time and the blood loss

The substance to be examined is administered orally as a suspension in a 1% adragant gum mucus with a Dose of 30 mg / kg Batten administered. The blood becomes 1 h or taken 3 hours after treatment. The plasma is separated off by centrifugation and the euglobolines are precipitated.

The fibrinolytic activity is determined according to the method of Astrup and Mullertz (Arch. Biochem. Biophys. 1952, 40, 346).

50 jul of a solution of euglobins in a veronal buffer, containing 0.25% gelatin were applied to fibrin plates at P.08%. After an incubation of 18 h at 37 ° O the diameter of the lysis zone was measured.

It was used as a puncture of the relationship between the fibrinolytic activity of treated rats and those of placebo-given rats had a score assigned the following meaning Has:

Score 4: coefficient of increase in fibronylitis Activity from 0.51 to 0.99.

Score 5 J coefficient of increase in Activity from 1 to 1.5.

Score 6: coefficient of increase in activity from 1.6 to 2.

Score 7: coefficient of increase in activity from 2.1 to 2.5.

Score 8: coefficient of increase in activity from 2.6 to 3.

Score 9: coefficient of increase in Activity over 3.1.

fibrinolytic fibrinolytic see see fibrinolytic fibrinolytic fibrinolyti

To determine the duration of bleeding, the tail of the rats, which were kept at ambient temperature for 2 hours, was cleaned with ether and cut 2 mm from the end with a scalpel. The duration of bleeding, given in seconds, was Measured 1 h or 3 h after the treatment. The blood was collected with filter paper. The amount of blood lost was determined by weighing the filter paper before and after taking the blood.

< i

The coefficient of increase in the duration of bleeding is the ratio between the duration of bleeding of treated Rats and those of rats given a placebo.

-je? - ■ ■

A score of 3 indicates an increase coefficient

from 0.79 to 0.89.

A score of 4 denotes an increase coefficient

from 0.9 to 1.09.

A score 5 indicates an increase coefficient

from 1.1 to 1.11.

A score 6 indicates an increase coefficient fc

from 1.12 to 1.22.

A score 7 indicates an increase coefficient

from 1.23 to 1.33.

A score 8 indicates an increase coefficient

from 1.34 to 1.44.

A point number 9 denotes an increase coefficient,

which is equal to or greater than 1.45.

The coefficient of increase in blood loss is the ratio between the amount of blood that is treated by Batten lost and those lost from control rats.

A score 3 indicates an increase coefficient;

less than or at most equal to 0.5 <

A score of 4 indicates an increase coefficient

from 0.51 to 0.99

A score 5 indicates an increase coefficient

from 1 to 1.5.

A score 6 indicates an increase coefficient

from 1.6 to 2.

A score 7 indicates an increase coefficient

from 2.1 to 2.5 «

A score of 8 pays an increase coefficient

from 2.6 to 3

A point number 9 denotes an increase coefficient,

which is equal to or greater than 3.1,

Two of the products according to the invention formed the article an in-depth study. It was derivative 7 and derivative 12 (free base of derivative 7 in hydrogenated form),

The compound 7 was the subject of a study by One month toxicity in rats and monkeys. This study showed that tolerability was up at a dose of 300 mg / kg / day is perfect.

The toxicity of compound 12 is excellent. The DL ₁ -Q is above 8 g / kg in mice and rats. It is completely tolerated by monkeys up to a dose of 800 mg / kg.

After oral administration of derivative 7 to groups of four rabbits at doses of 2.5 to 50 mg / kg, an increase in fibrinolytic activity was observed of the blood proportional to the dose administered. This increase is, for example, three times 90 minutes after the administration of 5 mg / kg. This effect shows up with repeated applications. So increases the Behändlurv; with 10 mg / kg, twice a day for 21 days, the fibrinolytic activity of the blood to a value that three times is higher than that of comparison animals.

With an intravenous perfusion of the derivative 12 in doses of 3 or 5 mg / kg / 10min for 2 hours * one observes Increase in fibrinolytic activity by 2.8 times, starting 10 to 30 minutes after the start of perfusion until at least 3 hours after the end of the persfusion.

The effect of compound 12 was also demonstrated in Had and monkeys recorded after oral administration. End-. Oral administration is also effective in humans from 100 to 800 mg an Ivrlib'hunr proportional to the dose: the fibrinolytic activity of the blood.

The daily dose for the administration of the new compounds according to the invention is 50 mg to 2 g for oral * ingestion and 10 mg to 1 g for intravenous injection or perfusion.

The products according to the invention can be used in various pharmaceutical forms. The following examples are not limiting and relate to pharmaceutical preparations that are an active product according to the invention contain that is denoted by the letter A, which can be for example calibrated

i-Oxo-2,2,5-trimethyl-i, ^ -thiazan ^ -carbonic acid ethyl ester, 2.2.4 _l 5-? etramethyl-1,4-thiazan-3-carbonic acid, 1- (pivaloxyloxy ) ethyleeter the

oxycarbonylnethyleeter,

1-0xo-2,2,5-trimethyl-1,4-thiazane-3-carboxylic acid-1-ethyl-

oxycarbonylethyleater, 5-butyl-2,2-dimethyl-i, ^ - thiazan ^ -carbonic acid,

2,2-dimethyl - $ - ieopropyl-1,4-thiazane-3-carboonic acid,

5 methyl ^ -phenyl-ij ^ -thiazan ^ -carbonic acid,

3-Carboxy-1,2-dimethyl-1,4-thiazan-5-eeBige acid ethyl ester.

Tablets

Jelly capsules

A. . 50.ng

Starch Sta BX 100 mg cellulose, microcrystalline 60 mg

Lactose, extra fine, crystalline. 132 mg silica, colloidal 2 mg

Castor oil, hydrogenated 6 mg

A 100 mg bicalcium phosphate 95 mg

Sodium strength 32.5 mg

Silica, colloidal 2 mg Magnesium stearate 0.5 mg

A. 500 mg Mannitol 95 mg Polyvinyl pyrrolidone 27 mg Polyethylene glycol 6000, powder 8 mg A. 300 mg strength 60 mg lactose I30 mg Low viscosity ethyl cellulose ? 0 mc talc 5 mg Aeroeil 5 dir;

Suppositories

A. (Semi-glyceride) 500 mg α-tocopherol solutions 10 mg Witepsol H 15 2600 mg Injectable A.

20 mg

Sodium chloride 2.5 mg

Citric acid / cibat buffer

Sodium compound ad pH 4.8 mg

Water for injections

ad 1 ml ■

Propylene glycol ethyl alcohol Water for injections

Jelly capsules dosed with 100 mg of compound A and acetylsalycylic acid ethyl cellulose lactose
Aerosi1
Magnesium stearate

50 mg 500 mg 50 mg ad 1 ml 300 mp; 60 mg 40 mg 8th mg 8th mg

.. "::: -θ '.: ί 3242655 69

300 mg 50 mg 25th . mg 100 mg

Tablets, dosed with 300 mg of compound A and 50 mg of dipyridamole

Dipyridamole hypromellose strength

Calcium stearate 8 mg

Tablets, dosed with 200 mg of compound A and 100 mg of suloctidil

Suloctidil Tween ethyl cellulose lactose Starch magnesium stearate

200 mg 100 nip 8th nip 22nd mg 40 mg 71 mg 9 mg

Claims (1)

Claims Derivative of 1,4-thiazane-3-carboxylic acid of the general formula R. R, C-R (D in which Mean R. and Rp, which may be the same or different, hydrogen, a linear or branched alkyl radical having 1, 2, or J ^l \ C-atoms or a phenyl radical optionally substituted by a halogen atom such as fluorine, chlorine or bromine, by a linear or branched alkyl radical with 1, 2, 3 or 4 carbon atoms or a linear or branched alkoxy radical with 1, 2, 3 or 4 carbon atoms is substituted, or R and Ro ⁰¹ ^ t the adjacent C- Atom forms a cycloalkyl radical with 3, 4, 5, 6, 7 or 8 carbon atoms, of which one or more carbon atoms can optionally be replaced by sulfur, oxygen or a group i30, SO ₀ or NIi ₀ , where in the latter R _{ß denotes} hydrogen, a linear or branched alkyl radical with 1, 2, 3 or 4 carbon atoms, a phenyl radical or a benzyl radical, R * is a hydroxyl group, an ORq group in which Rq a linear or branched alkyl group with 1, 2, 3, ■ 4v5, · .6, 7, 8, 9i 10, 11 or 12 carbon atoms or one Group 0-CH-COOR .. or a group OCH-OCOR. ■ ^R 10 ^ß 10 means in the R.q hydrogen or an alkyl radical with 1 or 2 carbon atoms and R ^ is a linear or branched alkyl radical with 1, 2, 3, 4, 5, 6, 7, 8, 9, Means 10, 11 or 12 carbon atoms, in which further , can be a group N, ^E 13 ' in which R ^ o ¹ ^ d H. ,, which can be the same or different , hydrogen or a linear or branched alkyl radical with 1, 2, 3 or 4 carbon atoms, a 3-phthalidyloxy or a 1- (2, 5-Dioxopyrrolidinyl) -1-ethoxy group, R. hydrogen, a linear or branched alkyl radical with 1, 2, 3, 4, 5i 6 »7 or 8 carbon atoms, ei -" * "" 'nen linear or branched acyl radical with 1, 2, 3, 4, 5 »6, 7 or 8 carbon atoms or the group CONHo means, or R-, and R .. with the neighboring carbon and t> 4 Nitrogen atoms form a hydantoin ring, R ₁ - and R ₆ , which can be identical or different, hydrogen, a linear or branched alkyl radical with 1, 2, 3, 4, 5, 6, 7 or 8 C-acomene, one optionally with a halogen atom such as fluorine, Chlorine ούβν 3242555 Bromine, phenyl radical substituted with a linear or branched alkyl radical with 1, 2, 5 or M carbon atoms or with a linear or branched alkoxy radical with 1, 2, 3 or 4 carbon atoms or a group CHpCOOR .., in which R ^ Is hydrogen or a linear or branched alkyl radical with 1, 2, 3 or 4 carbon atoms, R _{9 is} hydrogen, a linear or branched alkyl group with 1, 2, 3 or 4 carbon atoms, a gem-dimethyl group or optionally with a halogen atom such as fluorine, chlorine or bromine, with a linear or branched alkyl radical 1, 2, 3 or 4 carbon atoms or phenyl substituted with a linear or branched alkoxy group with 1, 2, 3 or ^ carbon atoms, n, has the value 0.1 or 2, R ₁ - and R _{c are} neither hydrogen nor a linear or branched alkyl radical having 1 to 4 carbon atoms or a phenyl radical when R _x J, R2, R ^ and R ₁ - are each oxygen and R is the hydroxyl group or a is a linear or branched alkyl radical with 1 to 4 carbon atoms, and the salts of these compounds with pharmaceutically acceptable acids and bases. Derivative according to claim 1, characterized in that in the general formula (I) R- and Rp, which are the same or can be different, denote hydrogen or the methyl radical. 3. A derivative according to one or the other of claims 1 or 2, characterized in that in the general formula (I) R, the hydroxyl group, an ORq group, in which Rq is a linear or branched alkyl radical having 1 to 4 carbon atoms, a group OCH-COOR ₁₁ or a ^R 10 means group OCHOCOR ₁₁ , in which R _{10 is} hydrogen ^fi 10 or the methyl radical and R ^ _{1 is} a linear or branched alkyl radical having 1 to 8 carbon atoms. 4. derivative according to any one of claims 1 to 3, characterized in that R. in the general formula (I) denotes hydrogen or the methyl radical. 5. A derivative according to any one of claims 1 to 4, characterized in that in the general formula (I) Rj- and Rg, which may be the same or different, hydrogen, a linear or branched alkyl radical having 1 to 4 carbon atoms or a group CHpCOOR ₁ ^, in which R ₁ ^ is hydrogen or an alkyl group with Λ or 2 carbon atoms. 6. derivative according to claim 5 ». Characterized in that in the general formula (I) R, - hydrogen and small linear or branched alkyl group with 1 to 4 carbon atoms mean. 7. A derivative according to any one of claims 1 bit .; G, characterized in that η has the value 0 or 1 in the general formula (I). 8. derivative according to claim 1, characterized in that it is formed from that of the following compounds Group is selected: 1-Oxo-2,2,5-trimethy1-1, ^ - thiazan-J-carboxylic acid-, i-Oxo-2,2,5-trimethy1-1, A-thiazan ^ -carbonsäure-e thy 1- ester, 2,2,4,5-tetramethyl-i, 4-thiazane-3-carboxylic acid, 1- (pivaloxyloxy) ethyl ester der i-Oxo-2,2,5-trimethy1-1,4-thiazanecarboxylic acid, 1-0xo-2,2,5-trimethy1-1, ^ - thiazane-3-carboxylic acid-octyl- oxycarbonyl methyl ester, i-Oxo-2,2,5-trimethyl-1, ^ - thiazane - ^ - carboxylic acid-i- ethyloxycarbonylethyl ester, p-Butyl-2,2-dimethyl-1, ^ - thiazane-J-carboxylic acid, 2,2-dimethyl-5-isopropyl-1,4-thiazane-3-carboxylic acid, 5-methyl-2-phenyl-1, ^ - thiazane-3-carboxylic acid, 3-carboxy-2,2-dimethyl-1,4-thiazan-5-acetic acid ethyl ester. 9. Intermediate products, in particular for the preparation of the derivatives according to any of the preceding Claims, according to the formulas Ro-C-CH 4 rm -ς ⁴ -C-CH / ^X NH-R ₄ ... ' NH-R ⁴ (O) S II III VI IS " where R ^, R £, ^R 3> ^R v ^R 5 ^'R g' ^R 7 ^{un (in} ei ⁿ © of the meanings given above. 10. Derivative as described above, in particular in the examples given in the description. 11. Process for the preparation of derivatives of 1,4-thiazane-3-carboxylic acid and salts thereof, thereby characterized in that a compound of the formula (II), of the formula (III) or compounds of the formulas (IV) and (V) cyclized in such a way that a compound of formula (I) is obtained: ^R l ^ COR-, ^R l ^ COR, R_ f- r υ JR r λ u ** ^ J (o) _n -sr ^R 4 (o) -sr ^R 4 XeC ' _N X) HCR ₅ R ^ ^R 6 R ₇ R / Y HS R ₇ -HC C ^ ^λ ■ ■ ^ R ₂ CH- COR IV .3 24 ze β in which formulas R ,. until R ₀ and η have the meanings given above, that intermediate products resulting from the cyclization are then subjected to a reduction in such a way that a derivative corresponding to formula (I) is obtained, after which the last product or the intermediate product and also the derivatives of the formula (I), which have been obtained starting from compounds of the formula (II) and of the formulas (IV) and (V), optionally an oxidation, an alkylation or an acylation on the substituent R ^ is subjected, or a substitution of this Substituents R ^ with a group CX) NH ^ * followed by a cyclization with the substituent Rx, if the last one is a hydroxyl group, so as to obtain a hydantoin group. 12. The method according to claim 11, characterized in that a derivative of the formula is used in a basic medium fl -COR, R _? -C CH ^ό / ^X . <° v ^s _v " ^{4 R} 7 cyclized. 13. The method according to claim 12, characterized in that an organic or inorganic base is used, such as triethylamine, N, N-dimethylaniline, pyridine, alkali metal hydroxide or ammonium hydroxide. 14. The method according to claim 11, characterized in that that one in the basic or dehydrating medium Derivative of the formula R ₁ ^ COR-, Rn - C C H ₍ o _{) n} .s - """ ¹ U cm) CH C - R, R ₇ R ₍ cyclized, in which X is a halogen atom such as chlorine, bromine or iodine, a hydroxyl group or an easily eliminated one Means group, such as a tosyl or mesyl group. 15. The method according to claim 11, characterized in that that a derivative of 5,6-dihydro-2H-thiazine of the formula ^ R (VI) COR ₃ : i O.XV 32426a§ reduced to a Ί, 4-thiazane of the formula (I), if necessary followed by an oxidation to produce the corresponding Sulfoxide or sulfone. 16. The method according to claim 15 »characterized in that that the derivative (VI) by a reaction between a cysteine derivative of the formula HS - C ¹ - CH - COR t ι · R ₂ NH ₂ and a ^ -halo ketone YCH-CORc, in which Y is a halogen atom such as chlorine, bromine or iodine. 17. The method according to claim 11, characterized in that for the preparation of a derivative of the formula (I), in the R. a linear or branched alkyl radical with 1 to 4 carbon atoms or a linear or branched acyl radical with 1 to 4 carbon atoms means a Amine of the formula (I), in which R ^ is hydrogen, subject to an alkylation or acylation with a compound R.Z in a basic medium, in which Z is a halogen atom such as chlorine, bromine or iodine or an easily eliminable group such as, for example Tosyl or Mesy! Group, means. 18. The method according to claim 11, characterized in that for the preparation of a derivative of the formula (I) in which .R ^ is the group CONH ₂ , a derivative of the formula (I) in which R ^ is hydrogen, with a Reacts compound of the formula MNCO, in which M is a monovalent cation, such as sodium, potassium, lithium or ammonium. 19. The method according to claim 11, characterized in that for the preparation of a derivative of the formula (1), in the R, and R ^ with the neighboring carbon and nitrogen atoms form a hydantoin ring, a compound of formula (I) in which R is the hydroxyl group and R ^ the group CONHpist, if necessary with heating exposed to an acidic environment. 20. The method according to claim 11, characterized in that that for the preparation of a derivative of the formula (I) in which η = 1 or 2, a derivative of the formula (I) is used where η = 0, treated with an oxidizing agent. 21. The method according to claim 20, characterized in that that the oxidation is effected at any stage in the production of the 1,4-thiazane ring. 22. The method according to claim 11, characterized in that a derivative of the formula (I) in which R, a Hydroxyl group means converted into a derivative by esterification, in which E, the group Means OCHCOOR ₁₁ or OCHOCOR ₁₁ . R ₁₀ R ₁₀ 25. The method according to claim 11, characterized in that a derivative of the formula (I) in which R, the hydroxyl group or a group ORq, OCHCOOR ₁₁ or ^B 10 is OCHOCOR ₁₁ , converted into a derivative by amidation «10 / E ₁₂ converts, in which R ^ is the group N. 24-. Process according to Claim 11, characterized in that a derivative of the formula (I) in which R ^ is the group ORq, OCHCOOR ₁₁ or OCHOCOR ₁₁ , by hydrolysis ^R 10 ^ß 10 or aminolysis is converted to a derivative in which fi, the hydroxyl group or the group N is.
^R 15 25. The method according to claim 11, characterized in that that a derivative of the formula (I) in which R, a Group N is by hydrolysis or alcoholysis is converted to a derivative in which R ₂ . a hydroxyl group or a group OR _Q , OCHCOOR ₁₁ or ^R 10 OCHOOOK-. is. 9i 26. Process for the preparation of derivatives of 1,4-thiazane-3-carboxylic acid and their salts as above described, in particular in the examples given in the description. 27. Pharmaceutical preparation, especially for the treatment and prevention of certain affections of the Circulatory system, such as venous or arterial thrombosis, characterized in that they contain at least one of the compounds of formula (I) or one of contains their salts, in conjunction with a suitable pharmaceutical carrier and, if necessary, durations therapeutic agents such as antiplatelet agents. . 28. Preparation according to claim 27, characterized in that that they are in the form of coated tablets, granules, tablets, capsules, solutions, syrups, emulsions or suspensions present, which contain the additives or carriers customary in galenic pharmacy. 29. Composition according to claim 27 or 28, characterized in that it contains at least one of the derivatives according to claim Λ in solution, insbesondei'e in sterile water, in peanut oil or ethyl oleate. 30. Method of using the derivatives ii-ich of the formula (I), in particular for the treatment and prevention of certain disorders of the circulatory system, such as venous or arterial thromboses, characterized in that they are taken orally in daily doses from 50 mg to 2 g and by intravenous injection or perfusion administered in daily doses of 10 mg to 1 g.